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Avicenna J Dent Res. 2015 June; 7(1): e23212.
Research Article
Published online 2015 March 20.
The Possible Role of Helicobacter pylori in the Development of Sjogren's
Syndrome and Chronic Sialadenitis
1
2,*
3
Alireza Monsef Esfahani ; Soussan Irani ; Shahram Sabeti ; Farahnaz Bidari Zerehpoush
3
1Department of Pathology, Hamadan University of Medical Sciences, Hamadan, IR Iran
2Department of Oral Pathology, Hamadan University of Medical Sciences, Hamadan, IR Iran
3Department of Pathology, Loghman Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
*Corresponding author: Soussan Irani, Department of Oral Pathology, Hamadan University of Medical Sciences, P. O. Box: 65178-38741, Hamadan, IR Iran. Tel: +98-8118354250, Fax:
+98-8118354220, E-mail: Address:sousanirani@gmail.com
Received: September 1, 2014; Revised: October 26, 2014; Accepted: November 2, 2014
Background: Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands,
which can be triggered by environmental factors such as viral infection. Chronic obstructive sialadenitis is the most common type of
chronic sialadenitis and many different bacterial infections develop as a result of ductal obstruction.
Objectives: This study was conducted to assess the association of these lesions with the presence of Helicobacter pylori.
Patients and Methods: A total of 56 biopsies diagnosed as Sjögren's syndrome (SS) and chronic sialadenitis (CS) due to sialolithiasis in
submandibular glands, sublingual and minor salivary glands were selected (56 samples as examined group and 20 samples as control
group). All the paraffin blocks were cut for hematoxylin and eosin (H and E) staining to confirm the diagnoses and then the samples were
prepared for immunohistochemistry (IHC) staining to detect H. pylori. Chi-squared test was used for statistical analysis.
Results: Chi-squared test showed a significant difference between H. pylori positivity in the groups examined (P = 0.046) and between
SS group and normal tissue samples (P = 0.013). There was no significant difference between gender and H. pylori positivity in examined
groups examined (P = 0.574, P = 0.543, respectively). In addition, there was no significant difference between gender and H. pylori positivity
in SS group (P = 0.119, P = 0.331, respectively) also in CS group (P = 0.981, P = 0.571).
Conclusions: Bacterial infection has been suggested in the pathogenesis of both SS and CS. In addition, H. pylori is a resident of the oral
cavity, thus may be involved in the development and progression of these lesions. Hence, search for H. pylori antibody in blood of patients
with SS is suggested.
Keywords:Sjogren’s Syndrome; Chronic Sialadenitis; Helicobacter pylori; Oral Cavity
1. Background
Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. It affects salivary glands and associated with
autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous and systemic sclerosis (1). SS is
one of non-infectious causes of salivary gland tissue inflammation (2). Patients with SS suffer from progressive
dryness of eyes and mouth due to insufficient salivary
and lacrimal secretions (3). In histological examination,
characteristic features of salivary glands can be seen including destruction of the acinar structure, total replacement of the salivary acinar structure by lymphocytic infiltrate, and also various changes in ductal structure such
as epimyoepithelial islands which can be seen mostly in
parotid gland tissue (2-4). According to previous studies,
sensitivity and specificity of the parotid biopsy is comparable with that of labial biopsy in diagnoses of SS (4).
In addition, patients with SS have an increased risk of
developing gastric lesions, such as gastric atrophy (5).
Previous studies showed chronic gastric inflammation
in 80% of patients with SS (6). In histopathological examinations, epithelial and glandular alterations are similar
to those of gastritis with H. pylori infection (7). Chronic
obstructive sialadenitis is the most common type of CS
(8). Periductal lymphocytic infiltration, acinar atrophy
and periductal fibrosis are the histological features of
chronic obstructive sialadenitis. Sialolithiasis is the most
common cause of chronic obstructive sialadenitis and
many different bacterial infections develop as a result
of ductal obstruction (2). H. pylori is a gram negative, spiral shaped organism, which colonizes in human gastric
mucosa. The association of H. pylori with pathogenesis
of peptic ulcers, gastric adenocarcinoma and low-grade
B-cell mucosa-associated lymphoid tissue lymphoma has
been proved (9).
Many studies indicated that H. pylori can be isolated
from the oral cavity, the dorsum of the tongue, salivary
secretions and dental plaque (supragingival plaque and
subgingival plaque) in patients with or without periodontitis (10, 11). H. pylori exists in the oral cavity even
Copyright © 2015, Hamadan University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial
usages, provided the original work is properly cited.
Monsef Esfahani A et al.
after systemic eradication therapy, suggesting that patients with positive results for gastric H. pylori have H. pylori in the oral cavity as well. Particularly in cases with gingivitis or periodontitis, the oral cavity can be considered
as a reservoir capable of increasing the risk of gastric
re-infection (12). The presence of H. pylori in some other
oral lesions has been reported. For example, in patients
with burning, halitosis and lingual dorsum hyperplasia,
87% of patients had positive results for H. pylori (13). In addition, in atrophic glossitis, benign migratory glossitis
and burning mouth syndrome, H. pylori was detected in
16% of patients (14). In one study, H. pylori was detected in
patients with aphthous stomatitis in 52% of cases (15). In
another study, 38.9% of patients with recurrent aphthous
stomatitis showed H. pylori positivity (16). Previous studies showed that SS was triggered by environmental factors such as a viral infection (17). infection has also been
also considered as an etiological factor in developing SS
and CS due to sialolithiasis (2).
2. Objectives
This study was conducted to assess the association of
these lesions with the presence of H. pylori.
3. Patients and Methods
A total of 56 biopsies diagnosed as Sjögren's syndrome
(SS) and chronic sialadenitis (CS) due to sialolithiasis in
submandibular, sublingual and minor salivary glands
and 20 tissue samples taken from the labial mucosa of
the lower lip and floor of mouth (as submandibular and
sublingual salivary glands excretory ducts drain to the
floor of mouth) with pathology report as “without significant pathological changes” were selected as the control group from the archive of Pathology Department of
Loghman Hospital, Tehran, Iran. All the paraffin blocks
were cut for H&E staining to confirm the diagnoses and
then the samples were prepared for IHC staining.
In brief, formalin-fixed, paraffin-embedded tissues were
all cut into 4 μm. The slides were then deparaffinized,
rehydrated and pre-treated with trypsin for 40 minutes
at 37°C according to manufacturer’s instructions (Novocastra, UK). The endogenous peroxidase activity was
blocked, followed by incubation with lyophilized rabbit
polyclonal antibody (Novocastra, UK) at a dilution of 1: 20
for one hour. DAB was used to visualize the complex. Finally, the sections were counterstained with haematoxylin and mounted. H. pylori positive and negative human
gastric samples served as positive and negative controls,
respectively. Statistical analysis was performed using
SPSS version 21.0.1, Chi-squared test and independentsamples T test were used. Significance was set at P < 0.05.
4. Results
In this study, there were 34 (44.7%) male and 42 (55.3%)
female. In general, the ages of patients and control group
ranged from 19 to 70 years, with a mean age of 38.83 years.
2
Demographic characteristics of samples and H. pylori detection status is summarized in Table 1. Chi-squared test
showed a significant difference between H. pylori positivity in the groups (P = 0.046) and between SS group and
normal tissue samples (P = 0.013). There was no significant difference between gender and H. pylori positivity
in examined groups (P = 0.574, P = 0.543, respectively).
In addition, there was no significant difference between
gender and H. pylori positivity in SS group (P = 0.119, P =
0.331, respectively) and in CS group (P = 0.981, P = 0.571).
Independent-Samples T test showed a significant difference between SS and CS groups and age (P = 0.002).
Table 1. Demographic Characteristics of Samples and H. pylori
Detection Status
Type of Lesion
Sjogren’s syndrome
No. of
Patients
Mean Age H. pylori
Range, y Positivity a
25
18 (72)
Male
5
45.40
Female
20
27-70
Chronic sialadenitis
31
17 (54.8)
Male
20
33.19
Female
11
19-46
Normal tissue
20
7 (35)
Male
9
39.35
Female
11
20-70
a Data are presented as No. (%).
5. Discussion
Exposure of bacteria to host tissues results in some
pathologic outcomes. Several immune effectors function
to minimize microbial interactions with host tissues (bacterial-epithelial contact). There is growing evidence from
animal models indicating that certain bacteria can trigger
immunopathology (18). The association between infection
and autoimmune diseases has been found previously (19).
Focal lymphocytic infiltration around the ducts is the
first histopathological feature in newly diagnosed SS
cases suggesting that antigen presentation of glandular
or acinar epithelium has a crucial role in SS pathogenesis
(20). Epithelial cells produce locally different B-cell targeted cytokines, and B-cell activating factor (BAFF) (21).
Previous investigations indicated that proinflammatory
cytokines such as IL-1 and IL-6 are produced by epithelial
cells and lymphocytes in SS, which strongly suggest that
both epithelial cells and lymphocytes (autoimmune epithelialitis) are important to initiate SS (22). On the other
hand, T-cell CD4 lymphoid hyperplasia in SS contributes
to B-cell hyperactivity due to exogenous or autoantigens.
In addition, B-cell activation is another finding in patients
with SS. Thus, in SS, T cells in the salivary glands must be
stimulated by antibodies, which enhance B cell proliferation (23). Growing evidence indicates that patients with
Avicenna J Dent Res. 2015;7(1):e23212
Monsef Esfahani A et al.
SS have an increased risk of lymphomas as well as gastric
lesions (5). In the current study, 72% of SS samples, 54.8%
of CS samples and 35% of normal tissues showed H. pylori
positivity in IHC staining (Table 1). The present study also
demonstrated a statistically significant difference in H.
pylori positivity between SS tissues and normal tissue
samples. Figure 1 shows the presence of H. pylori in both
SS and CS samples.
Figure 1. Presence of H. pylori in Both Sjogren’s Syndrome and Chronic
Sialadenitis Samples
In a study on patients with SS (primary and secondary)
carried out by El Miedany et al. it was shown that prevalence of H. pylori infection and average titers of anti-H. pylori antibodies were significantly higher compared to patients with connective tissue diseases or healthy control
subjects. Due to a high prevalence of H. pylori infection
in the studied group, the authors considered a significant correlation between H. pylori infection and disease
duration, and suggested that the longer the duration of
SS, the greater the likelihood of having H. pylori infection
in patients (24). Aragona et al. working on patients with
different autoimmune diseases showed that 79.4% of patients with primary SS had antibodies against H. pylori
and there was also a significant difference between the
SS group and patients with various autoimmune diseases regarding H. pylori serum antibody (25). Banno et al.
found H. pylori antibody in 75.5% of SS patients. There was
also a significant difference between the level of H. pylori
antibody in patients and control groups (26).
Previous investigations demonstrated that H. pylori can
produce extracellular products that cause local and systemic immune responses resulting in tissue damage (27).
H. pylori infection induces a humoral response which may
contribute to surrounding tissues damage (28). H. pylori
pathogenesis acts through two mechanisms. Firstly, H.
Avicenna J Dent Res. 2015;7(1):e23212
pylori interaction with surface epithelial cells develops
direct cell damage or produces pro-inflammatory mediators (29). Secondly, H. pylori reaches the underlying
mucosa, hence stimulates immune response, which in
turn leads to liberation of different cytokines and oxygen radicals (30). The presence of H. pylori in the lamina
propria has been proven indicating H. pylori invasion to
the underlying tissues, induction and development of inflammation (31). In addition, H. pylori was detected inside
the blood vessels, which may explain H. pylori bacteremia
and systemic responses (32). Ito et al. found that H. pylori
is able to pass through the endothelial layer (31). Endothelial cell injury may induce vasculitis, which results in the
release of inflammatory mediators and systemic immune
response (33). Within H. pylori infected gastric mucosa,
IL-8 is increased (34). CD4+ T cells migrate to gastric mucosa and cause epithelial damage through proliferation,
apoptosis and metaplasia (35). This might be caused by a
direct bacterial effect like IL-8 or as a consequence of cellular immune response (36). CD4 T cell absence in H. pylori associated gastritis leads to increased gastritis dominated by an infiltration of CD8 T cells (37). Thus, it seems
that CD8 T cells contribute to H. pylori-induced pathology.
H. pylori antigen-presenting cells have interactions with
CD4-expressing cells, which bind to B-cells in the marginal zone leading to T-cell activation, lymphoid follicle
formation, and B-cell proliferation in gastric mucosa and
therefore development of gastric lymphoma (38).
Patients with SS also have over a 44-fold increased risk
of development of B-cell non-Hodgkin’s lymphoma (39).
There is some evidence of gastric and parotid MALT lymphoma regression after H. pylori eradication (40). It was
suggested that possible mechanisms for infection could
be direct infection of salivary gland tissue by H. pylori or
recirculation of organism related antigens from another
site of infection (41). Taken together, it is suggested that
during H. pylori related MALT lymphomas, there is a close
interaction among epithelial cells, T cells and B cells.
In conclusion, bacterial infection has been suggested
in the pathogenesis of both SS and CS. In addition, H. pylori is a resident of theoral cavity, thus can be involved in
development and progression of these lesions. It is suggested to search for the H. pylori antibody in the blood of
patients with SS. Regarding the high risk of MALT in patients with SS, which had regressed after H. pylori eradication, eradication of H. pylori in these patients can be helpful for patient survival, especially in the early stages of SS.
Funding/Support
This study was supported by a Grant from the Hamadan
University of Medical Sciences.
References
1.
2.
Theander E, Jacobsson LT. Relationship of Sjogren's syndrome to
other connective tissue and autoimmune disorders. Rheum Dis
Clin North Am. 2008;34(4):935–47.
Neville BW, Damm DD, Allen CM, Bouquot JE:. Oral & Maxillofacial
3
Monsef Esfahani A et al.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
4
Pathology. 3 edUSA: W.B.Saunders; 2009.
Hayashi T. Dysfunction of lacrimal and salivary glands in Sjogren's syndrome: nonimmunologic injury in preinflammatory
phase and mouse model. J Biomed Biotechnol. 2011;2011:407031.
Pijpe J, Kalk WW, van der Wal JE, Vissink A, Kluin PM, Roodenburg
JL, et al. Parotid gland biopsy compared with labial biopsy in the
diagnosis of patients with primary Sjogren's syndrome. Rheumatology (Oxford). 2007;46(2):335–41.
Ostuni PA, Germana B, Di Mario F, Rugge M, Plebani M, De Zambiasi P, et al. Gastric involvement in primary Sjogren's syndrome.
Clin Exp Rheumatol. 1993;11(1):21–5.
Kilpi A, Bergroth V, Konttinen YT, Maury CP, Reitamo S, Wegelius
O. Lymphocyte infiltrations of the gastric mucosa in Sjogren's
syndrome. An immunoperoxidase study using monoclonal antibodies in the avidin-biotin-peroxidase method. Arthritis Rheum.
1983;26(10):1196–200.
Ebert EC. Gastrointestinal and hepatic manifestations of Sjogren
syndrome. J Clin Gastroenterol. 2012;46(1):25–30.
Seifert G. Aetiological and histological classification of sialadenitis. Pathologica. 1997;89(1):7–17.
Kim SS, Ruiz VE, Carroll JD, Moss SF. Helicobacter pylori in the
pathogenesis of gastric cancer and gastric lymphoma. Cancer
Lett. 2011;305(2):228–38.
Gebara EC, Pannuti C, Faria CM, Chehter L, Mayer MP, Lima LA.
Prevalence of Helicobacter pylori detected by polymerase chain
reaction in the oral cavity of periodontitis patients. Oral Microbiol Immunol. 2004;19(4):277–80.
Riggio MP, Lennon A. Identification by PCR of Helicobacter pylori
in subgingival plaque of adult periodontitis patients. J Med Microbiol. 1999;48(3):317–22.
Morales-Espinosa R, Fernandez-Presas A, Gonzalez-Valencia G,
Flores-Hernandez S, Delgado-Sapien G, Mendez-Sanchez JL, et al.
Helicobacter pylori in the oral cavity is associated with gastroesophageal disease. Oral Microbiol Immunol. 2009;24(6):464–8.
Adler I, Denninghoff VC, Alvarez MI, Avagnina A, Yoshida R, Elsner B. Helicobacter pylori associated with glossitis and halitosis. Helicobacter. 2005;10(4):312–7.
Gall-Troselj K, Mravak-Stipetic M, Jurak I, Ragland WL, Pavelic J.
Helicobacter pylori colonization of tongue mucosa--increased
incidence in atrophic glossitis and burning mouth syndrome
(BMS). J Oral Pathol Med. 2001;30(9):560–3.
Mansour-Ghanaei F, Asmar M, Bagherzadeh AH, Ekbataninezhad
S. Helicobacter pylori infection in oral lesions of patients with recurrent aphthous stomatitis. Med Sci Monit. 2005;11(12):CR576–9.
Victoria JM, Kalapothakis E, Silva Jde F, Gomez RS. Helicobacter
pylori DNA in recurrent aphthous stomatitis. J Oral Pathol Med.
2003;32(4):219–23.
Low HZ, Witte T. Aspects of innate immunity in Sjogren's syndrome. Arthritis Res Ther. 2011;13(3):218.
Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science.
2012;336(6086):1268–73.
Amital H, Govoni M, Maya R, Meroni PL, Ori B, Shoenfeld Y, et al.
Role of infectious agents in systemic rheumatic diseases. Clin Exp
Rheumatol. 2008;26(1 Suppl 48):S27–32.
Voulgarelis M, Tzioufas AG. Current Aspects of Pathogenesis in
Sjogren's Syndrome. Ther Adv Musculoskelet Dis. 2010;2(6):325–34.
Vogelsang P, Jonsson MV, Dalvin ST, Appel S. Role of dendritic
cells in Sjogren's syndrome. Scand J Immunol. 2006;64(3):219–26.
Moutsopoulos HM. Sjogren's syndrome: autoimmune epithelitis. Clin Immunol Immunopathol. 1994;72(2):162–5.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
Youinou P, Devauchelle-Pensec V, Pers JO. Significance of B cells
and B cell clonality in Sjogren's syndrome. Arthritis Rheum.
2010;62(9):2605–10.
El Miedany YM, Baddour M, Ahmed I, Fahmy H. Sjogren's syndrome: concomitant H. pylori infection and possible correlation
with clinical parameters. Joint Bone Spine. 2005;72(2):135–41.
Aragona P, Magazzu G, Macchia G, Bartolone S, Di Pasquale G,
Vitali C, et al. Presence of antibodies against Helicobacter pylori
and its heat-shock protein 60 in the serum of patients with Sjogren's syndrome. J Rheumatol. 1999;26(6):1306–11.
Banno S, Matsumoto Y, Sugiura Y, Yoshinouch T, Shibata H, Ueda
R. Seroprevalence ofHelicobacter pylori and association with
atrophic gastritis in patients with Sjögren’s syndrome. Jpn J
Rheumatol. 1999;9(4):353–63.
Perez-Perez GI, Dworkin BM, Chodos JE, Blaser MJ. Campylobacter
pylori antibodies in humans. Ann Intern Med. 1988;109(1):11–7.
Farinha P, Gascoyne RD. Helicobacter pylori and MALT lymphoma. Gastroenterology. 2005;128(6):1579–605.
Naumann M, Crabtree JE. Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis. Trends Microbiol.
2004;12(1):29–36.
Baik SC, Youn HS, Chung MH, Lee WK, Cho MJ, Ko GH, et al. Increased oxidative DNA damage in Helicobacter pylori-infected
human gastric mucosa. Cancer Res. 1996;56(6):1279–82.
Ito T, Kobayashi D, Uchida K, Takemura T, Nagaoka S, Kobayashi I,
et al. Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes. Lab Invest. 2008;88(6):664–81.
Ndawula EM, Owen RJ, Mihr G, Borman P, Hurtado A. Helicobacter
pylori bacteraemia. Eur J Clin Microbiol Infect Dis. 1994;13(7):621.
Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine
(Baltimore). 2002;81(2):139–53.
Crabtree JE, Peichl P, Wyatt JI, Stachl U, Lindley IJ. Gastric interleukin-8 and IgA IL-8 autoantibodies in Helicobacter pylori infection. Scand J Immunol. 1993;37(1):65–70.
Peterson RA, 2nd, Hoepf T, Eaton KA. Adoptive transfer of splenocytes in SCID mice implicates CD4+ T cells in apoptosis and
epithelial proliferation associated with Helicobacter pylori-induced gastritis. Comp Med. 2003;53(5):498–509.
Peek RM, Jr, Fiske C, Wilson KT. Role of innate immunity in
Helicobacter pylori-induced gastric malignancy. Physiol Rev.
2010;90(3):831–58.
Tan MP, Pedersen J, Zhan Y, Lew AM, Pearse MJ, Wijburg OL, et al.
CD8+ T cells are associated with severe gastritis in Helicobacter
pylori-infected mice in the absence of CD4+ T cells. Infect Immun.
2008;76(3):1289–97.
D'Elios MM, Amedei A, Manghetti M, Costa F, Baldari CT, Quazi AS,
et al. Impaired T-cell regulation of B-cell growth in Helicobacter
pylori--related gastric low-grade MALT lymphoma. Gastroenterology. 1999;117(5):1105–12.
Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R,
Jacobsson LT. Lymphoma and other malignancies in primary Sjogren's syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796–803.
Iwai H, Nakamichi N, Nakae K, Konishi M, Inaba M, Hoshino S,
et al. Parotid mucosa-associated lymphoid tissue lymphoma
regression after Helicobacter pylori eradication. Laryngoscope.
2009;119(8):1491–4.
Walt RP. Regression of MALT lymphoma and treatment for Helicobacter pylori. Lancet. 1996;348(9033):1041–2.
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